Sialic acids are a diverse family of carbohydrate moieties that are common modifications found on proteins and lipids. Serum sialoproteins are important mediators of inflammation, a process that has been linked to colon cancer. Since all sialoproteins are modified with sialic acid, the total serum sialic acid level has been studied for use as a biomarker of inflammation. However, less attention has been given to the specific type and linkage of the individual sialic acid modifications. In part, this is due to the original misconception that the hepatic asialoglycoprotein receptor (ASGP-R) mediates the clearance of circulating sialoproteins only after they have been desialylated. If desialylated proteins were the major endogenous ligands, then ASGP-R ablated mice would be expected to have elevated serum levels of desialylated proteins. However, these mice do not have elevated levels of desialylated proteins and suggests alternative in vivo ligands. Our recent research showed that the ASGP-R binds 12,6-linked sialic acids on glycoconjugates and suggests that in vivo ligands for this receptor are serum sialoproteins. This raises the possibility that in vivo the ASGP-R mediates the clearance of inflammatory serum sialoproteins. This clearance is likely to be affected by dietary components that can induce the synthesis of sialic acids and thus increase sialic acid modification of proteins. Diet is another potential source of sialic acids, including the non-human sialic acid N-glycolylneuraminic acid (NGNA) which is highly abundant in red meat products. Currently, it is not known whether sialoproteins bearing NGNA are recognized by the human ASGP-R. In this R21 proposal, we will study the recently discovered sialic acid-binding property of the ASGP- R in order to establish that the ASGP-R mediated clearance of sialoproteins is a mechanism that links dietary components and the inflammation process. PUBLIC HEALTH RELEVANCE: Changes in the circulating levels of serum proteins are the focus of many studies that are looking for better biomarkers for healthy and diseased states in humans. However, after proteins are secreted into the circulation, there is a fundamental lack of knowledge about how these circulating proteins are removed from the circulation. This proposal is designed to test a novel mechanism for how a majority of circulating proteins may be removed from the circulation.